Coeli­acs yearn for ge­net­ics to win the bat­tle

Re­search into coeliac dis­ease of­fers the hope that non-di­etary treat­ments could be tai­lored to a per­son’s genes, writes Lyn­nette Hoff­man

The Weekend Australian - Travel - - Health -

EVER since she was di­ag­nosed with coeliac dis­ease a year ago, So­phie Stone has dili­gently stuck to the gluten-free diet re­quired to keep symp­toms at bay. She checks food la­bels re­li­giously, in­ter­ro­gates wait­ing staff at restau­rants as soon as she ar­rives, and ex­plains her sit­u­a­tion to any­one who in­vites her in for a meal. But awk­ward sit­u­a­tions still arise.

A re­cent din­ner comes to mind. The hosts had taken great care to en­sure that gluten — a sticky pro­tein found in wheat, rye, bar­ley and oats — wasn’t on the menu. They’d pre­pared all sorts of meat to bar­be­cue and even made a gluten-free pasta salad. But they’d forgotten to check in­gre­di­ents in the mari­nade — and many typ­i­cal mari­nade sta­ples, such as soy sauce and oys­ter sauce, con­tain gluten. This one was no ex­cep­tion.

Not want­ing to in­sult them, Stone ate the meat — and spent much of the night in the bath­room feel­ing its ef­fects.

Iron­i­cally, be­fore she stopped eat­ing gluten, Stone suf­fered few of the gas­tro-in­testi­nal symp­toms that char­ac­terise the dis­ease. But now she’s hy­per­sen­si­tive, and even trace amounts make her sick.

In coeliac dis­ease, which can de­velop at any age, gluten trig­gers an im­mune re­sponse that dam­ages the small in­tes­tine. The villi, the fin­ger-like pro­jec­tions that line the small in­tes­tine and ab­sorb the nu­tri­ents you eat, be­come flat­ter, shorter, and in some cases are lost com­pletely. It’s that vis­i­ble phys­i­cal dam­age that dis­tin­guishes coeliac dis­ease from the more com­mon gluten in­tol­er­ance, where a per­son ex­pe­ri­ences se­vere gas­troin­testi­nal prob­lems from gluten.

When the villi be­come dam­aged the abil­ity to ab­sorb nu­tri­ents is dra­mat­i­cally re­duced, leav­ing peo­ple prone to iron de­fi­ciency, fa­tigue, low bone den­sity, os­teo­poro­sis and in­fer­til­ity. It can be es­pe­cially dan­ger­ous in un­di­ag­nosed preg­nant women, whose fe­tuses might not be get­ting the vi­ta­mins and min­er­als they need, putting them at dou­ble the risk of ad­verse out­comes and birth de­fects such as spina bi­fida.

Cur­rently the only avail­able treat­ment is a life-long gluten-free diet, and while it works to pre­vent in­testi­nal dam­age and mal­nu­tri­tion, it is no cure and leaves pa­tients vul­ner­a­ble if they con­sume gluten by mis­take. And a gluten-free diet isn’t easy.

Stone can tes­tify to that. Gluten-free di­ets are gain­ing pop­u­lar­ity so suit­able prod­ucts are in­creas­ingly avail­able, but they are sig­nifi- cantly more ex­pen­sive. Take gluten-free bread, for ex­am­ple. ‘‘ It’s out there, but nine times out of 10 you’ll pay some­thing like $7 for a loaf that’s half the size (of nor­mal bread),’’ Stone says. Pasta is about four times the price.

It’s not just about price. Gluten is one of the com­po­nents of wheat flour that helps to make dough stick to­gether, so bread, pasta and other prod­ucts made with­out it have an unfamiliar — many would say un­pleas­ant — tex­ture.

Many gluten-free breads are crumbly, like stale cake with­out the sugar. As for the pasta, you have to watch it closely or it falls apart, she says. And the taste? Stone says she has fi­nally found a gluten-free bread she can en­dure, but in gen­eral it’s much heav­ier and more dense. But the real frus­tra­tion is the has­sle. ‘‘ It lim­its my whole lifestyle. You don’t have as much free­dom to be spon­ta­neous,’’ she says. Even foods that are in the­ory gluten-free, such as hot chips, may not be, if, for ex­am­ple, the oil they’ve been cooked in has been tainted with other prod­ucts such as bat­tered fish.

In a per­son with coeliac dis­ease, con­sum­ing just 50mg of gluten — about the same as 1/100th of a slice of bread — is enough to dam­age the small in­tes­tine.

If there was an al­ter­na­tive treat­ment avail­able, Stone says she’d be among the first to put her hand up for it.

Now Vic­to­rian re­search pub­lished in the cur­rent is­sue of the jour­nal Im­mu­nity has shed new light into the way the dis­ease works at a molec­u­lar level, bring­ing closer the pos­si­bil­ity of new non-di­etary treat­ments ( Im­mu­nity 2007;27:1-12).

The study shows that a per­son’s im­mune re­sponse dif­fers de­pend­ing on the par­tic­u­lar genes they have — mean­ing that to be ef­fec­tive, treat­ments would need to be tai­lored for the dif­fer­ent gene com­bi­na­tions most com­monly found in peo­ple with the dis­ease.

There’s a strong ge­netic link in coeliac dis­ease. Al­most all pa­tients (99.6 per cent) have ei­ther a gene known as DQ2, a gene called DQ8, or both — al­though they alone don’t cause the dis­ease. Thirty to 40 per cent of the pop­u­la­tion has ei­ther one of those genes, but only 1 per cent has coeliac dis­ease, mean­ing en­vi­ron­men­tal fac­tors also play a role. Some peo­ple — such as those whose fam­ily mem­bers have al­ready been di­ag­nosed with the dis­ease, as well as peo­ple with type 1 di­a­betes or thy­roid dis­ease, are also at a higher risk of coeliac dis­ease.

Un­til now nearly all re­search into nondi­etary treat­ments of coeliac dis­ease fo­cused on the 80 per cent of peo­ple who have only the DQ2 gene. Re­searchers had al­ready fig­ured out the process that made gluten toxic in peo­ple with DQ2-as­so­ci­ated coeliac dis­ease and as­sumed it would be much the same for the mi­nor­ity of peo­ple with the DQ8 ver­sion.

They as­sumed any po­ten­tial treat­ment could ap­ply to ei­ther. But it turns out that’s not the case, says doc­tor Bob An­der­son, a gas­troen­terol­o­gist at the Wal­ter and El­iza Hall In­sti­tute, and an au­thor of the latest study.

‘‘ This is the first time we’ve be­gun to look be­yond the core 80 to 90 per cent of peo­ple with coeliac dis­ease who have the DQ2 gene — the DQ8 have been slightly over­looked,’’ An­der­son says. ‘‘ At the molec­u­lar level there’s quite a dif­fer­ent im­mune re­sponse to the gluten.’’

For ex­am­ple, in peo­ple with DQ2-as­so­ci­ated coeliac dis­ease, parts of the pro­tein that trig­ger an im­mune re­sponse aren’t be­ing prop­erly di­gested. Be­cause peo­ple with coeliac dis­ease are hy­per-sen­si­tive to gluten, their T cells recog­nise the undi­gested bits as in­vad­ing pathogens, and re­spond ag­gres­sively. Some sci­en­tists are look­ing at how enzymes could break down the pro­tein bet­ter and re­duce the im­mune re­sponse.

‘‘ In peo­ple with DQ8, the rel­e­vant parts of the gluten are al­ready ef­fi­ciently di­gested, so us­ing an en­zyme wouldn’t nec­es­sar­ily be ben­e­fi­cial,’’ An­der­son says.

So one of the pos­si­ble treat­ments re­searchers are look­ing at is a de­sen­si­ti­sa­tion vac­cine that would use the parts of the pro­tein that are specif­i­cally rel­e­vant to DQ8 to shut down the T-cell so it be­comes tol­er­ant of the gluten. Sci­en­tists at the Wal­ter and El­iza Hall In­sti­tute are cur­rently work­ing on an­other ver­sion of the vac­cine aimed at the DQ2 gene.

In the last four years doc­tors have been us­ing a gene test to rule out coeliac dis­ease — but to ac­tu­ally make a di­ag­no­sis they need a biopsy of the bowel to look for signs of dam­age. Ul­ti­mately re­searchers hope the gene test will help doc­tors de­cide what treat­ment the pa­tient would ben­e­fit most from.

But any non-di­etary treat­ment is still at least a few years away, An­der­son says, so for now the gluten-free diet is it.

When coeliac pa­tients man­age to com­pletely avoid gluten, their in­tes­tine does heal. So if you sus­pect you may have coeliac dis­ease, ex­perts say you should not cut out gluten un­less you’ve ac­tu­ally had a biopsy to make the di­ag­no­sis. If you do it the other way around you may get a false neg­a­tive, says Sue Shep­herd a di­eti­tian in the de­part­ment of gas­troen­terol­ogy at Box Hill Hospi­tal, who spe­cialises in ce­o­liac dis­ease.

‘‘ It varies, but it can take up to two years for the small bowel lin­ing to fully heal,’’ Shep­herd says, while the gas­troin­testi­nal symp­toms can dis­ap­pear much more quickly.

‘‘ For some peo­ple they are gone af­ter the first few days of a gluten-free diet and for oth­ers it takes months. Symp­toms of fa­tigue can also im­prove in a mat­ter of weeks for some peo­ple, or months for oth­ers.’’

Com­mon symp­toms of coeliac dis­ease in­clude bloat­ing, wind, pain, di­ar­rhoea or con­sti­pa­tion or both, fa­tigue and iron de­fi­ciency.

‘‘ Peo­ple can eat gluten with­out feel­ing un­well, but still be caus­ing dam­age on the inside,’’’ Shep­herd says.

In fact, she says, there is no link be­tween the sever­ity of symp­toms and the amount of dam­age to your small in­tes­tine. Re­search she did as part of her PhD that looked at 101 coeliac pa­tients found 30 per cent had no symp­toms — but 82 per cent of that group had se­ri­ous dam­age to their in­tes­tine.

No mat­ter how mild or silent the symp­toms, ev­ery­one di­ag­nosed with coeliac dis­ease ‘‘ re­quires the same strict life-long gluten free diet’’, Shep­herd says. At least for now.

Pic­ture: Michael Pot­ter

Com­pro­mised: So­phie Stone says coeliac dis­ease al­most pro­hibits spon­tane­ity in her life

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